ABSTRACT Epidemiologic studies have linked obesity to poor breast cancer outcomes, and it has been suggested that obese women may experience poorer outcomes, in part, due to inadequate dosing of cytotoxic agents among obese women. Specifically, most cytotoxic agents are dosed according to body surface area, and therefore, the larger the woman, the higher the absolute dose. However, evidence shows that clinicians are more likely to depart from recommended dosing among heavier women for fear of inducing chemotherapy-associated toxicity. In 2012, the American Society of Clinical Oncology (ASCO) released guidelines stating that obese women should be dosed according to their full body surface area, largely based on evidence that suggested that fully- dosed obese women do not appear to experience more toxicity than fully-dosed normal-weight women. However, the guidelines acknowledge that data are extremely limited with regard to more severe obesity and in the real-world context of comorbidities. Furthermore, these guidelines cite that this practice of `dose reducing' obese women may be one reason contributing to the poorer outcomes observed in this group. However, to date, no empirical investigations have sought to determine if, and to what extent, dose-reduced chemotherapy may explain differences in breast cancer survival. These guidelines were met with some criticism, citing the need for further evidence, and data suggest continuing uncertainty about proper dosing of obese cancer patients. Understanding the drivers of dose reductions may help better inform our understanding of this practice and efforts to disseminate guidelines; however, we know little about factors driving dose intensity, and how these factors may vary by body size. We therefore propose to address these gaps using data on nearly 34,000 Stage I-IIIA breast cancer patients diagnosed and treated at Kaiser Permanente Northern California and at Group Health. Specifically, we will use the rich data from these integrated healthcare delivery systems to examine the relationship between body size and dose intensity, and will further examine how the factors contributing to dose reductions vary by body size (Aim 1). We will also evaluate if, and to what extent, dose reductions mediate the association between obesity and breast cancer recurrence and survival (Aim 2). Lastly, we will evaluate the association between body size and toxicity among women identified as receiving the full BSA-determined dose of chemotherapy (Aim 3). Our findings will provide critical and timely information to support or to warrant modification of current recommendations for chemotherapy dosing for obese breast cancer patients. Given the high and increasing prevalence of obesity in the United States, it is critical that we improve our understanding of chemotherapy dosing. The knowledge gained from this study can be used to better inform optimal treatment for the estimated 102,000 obese women diagnosed with breast cancer each year in the United States.